Article Published in the Author Account of

Javier Conde

Adipokines: Novel Players in Rheumatic Diseases

Abstract: A large body of evidence from clinical and experimental studies is aiding to understand the close relationships between obesity and rheumatic diseases. For instance, it is generally accepted that obesity contributes to the development of osteoarthritis by increasing mechanical load of the joints, at least in weight bearing joints. However, besides mechanical effects, recent studies demonstrated that white adipose tissue is able to secrete a plethora of soluble factors, called adipokines, which have a critical role in the development and progression of some rheumatic diseases such as osteoarthritis and rheumatoid arthritis. In this article, we summarize the recent findings on the interaction of certain adipokines with the two most common rheumatic diseases: osteoarthritis and rheumatoid arthritis.



Introduction

Up to the discovery of leptin in 1994 by Zhang et al. (1994), white adipose tissue (WAT) was considered only an energy storage tissue. In the recent years, WAT has been recognized to be a true endocrine organ, which is able to secrete a wide variety of factors termed adipokines (Hotamisligil et al., 1993; Fantuzzi, 2005). In addition to their metabolic activities recognized initially, these adipose-derived factors represent a new family of compounds that are also synthesized in other tissues, in addition to WAT, which could participate in several processes including inflammation and immunity (Otero et al., 2005; Tilg and Moschen, 2006; Lago et al., 2007).

Adipokines include a variety of pro-inflammatory factors with most of them being increased in obesity and appearing to contribute to the so-called “low-grade inflammatory state” in obese subjects. Inflammation in obesity is also closely related to a cluster of metabolic disorders including cardiovascular complications and autoimmune inflammatory diseases.

Apart from its metabolic activities, adipokines can be currently considered as key players of the complex network of soluble mediators involved in the pathophysiology of rheumatic diseases. Obesity, the condition that spurred the research on adipokines, has been considered a risk factor for developing osteoarthritis (OA) (Edwards et al., 2012; Vincent et al., 2012). It has been reported that obesity increases the incidence of OA, particularly in weight-bearing joints such as knees (Wluka et al., 2012), but the fact that obese subjects have an increased risk of OA in non-weight bearing joints such as hands (Yusuf et al., 2010; Grotle et al., 2008) reveals that soluble factors, adipokines indeed, are at play in the onset and progression of this rheumatic disease.

This review summarizes the current data concerning the involvement of certain adipokines in the two main rheumatic diseases, osteoarthritis and rheumatoid arthritis (RA).

Leptin

Leptin is a 16 kDa non-glycosylated hormone that is encoded by the obese (ob) gene, the murine homolog of human LEP gene (Zhang et al., 1994). Leptin exerts its biological actions through the activation of its OB-Rb long-form receptor isoform that is encoded by the gene diabetes (db) and belongs to the class 1 cytokine receptor superfamily. It is mainly produced by adipocytes, and its circulating levels are correlated with WAT mass. Mutation in either ob gene or the gene encoding the leptin receptor (the diabetes, or db gene), results in severe obesity. This hormone decreases food intake and increases energy consumption by acting on specific hypothalamic nuclei, inducing anorexigenic factors such as cocaine amphetamine related transcript (CART) and suppressing orexigenic neuropeptides such as neuropeptide Y (Ahima et al., 1996). Leptin levels are mostly dependent on the amount of body fat, but its synthesis is also regulated by inflammatory mediators (Gualillo et al., 2000).

Leptin and Osteoarthritis

It is increasingly evident that this hormone plays a key role in the OA pathophysiology; in fact serum leptin levels are increased in OA patients (de Boer et al., 2012). Some initial findings have suggested an anabolic role of this hormone in the cartilage (Dumond et al., 2003). But most studies revealed a catabolic role of leptin at cartilage level. For instance, our group demonstrated for the first time that, in cultured human and murine chondrocytes, type 2 nitric oxide synthase (NOS2) is synergistically activated by the combination of leptin plus interferon-γ. Next, we demonstrated that NOS2 activation by interleukin-1β (IL-1β) is increased by leptin via a mechanism involving JAK2, PI3K, and mitogen activated kinases (MEK1 and p38) (Otero et al., 2003; 2005). Nitric oxide (NO), which is induced by a wide range of pro-inflammatory cytokines, is a well-known pro-inflammatory mediator on joint cartilage, where it triggers chondrocyte phenotype loss, apoptosis, and activation of metalloproteinases (MMPs).

Recently, it has been demonstrated that leptin is able to also induce the expression of MMPs involved in OA cartilage damage, such as MMP-9 and MMP-13 (Toussirot et al., 2007). In fact, conditioned media from osteoarthritic infrapatellar fat pad, containing leptin, induce the synthesis of certain MMPs (Hui et al., 2012), demonstrating that the local production of leptin participates in the degradation processes occurred in the joints. More lines of evidence suggested that leptin, alone and in combination with IL-1β, up-regulates MMP-1 and MMP-3 production in human OA cartilage through the transcription factor NF-κB (nuclear factor κB), protein kinase C, and MAP kinase pathways. This adipokine is also correlated positively to MMP-1 and MMP-3 in synovial fluid (SF) from OA patients (Koskinen et al., 2011b). Moreover, recently leptin has been demonstrated to increase IL-8 production in human chondrocytes (Gomez et al., 2011). Bao et al. (2010) have defined that leptin enhanced both gene and protein levels of catabolic factors such as MMP-2 and MMP-9, while down-regulated the anabolic factors such as basic fibroblast growth factor (bFGF) in articular cartilage of rats. Additionally, the gene expression of ADAMTS-4 and -5 were markedly increased and a depletion of proteoglycan in articular cartilage was observed after treatment with leptin.

More recently, our group demonstrated that leptin per se is also able to increase the expression of vascular cell adhesion molecule-1 (VCAM-1), a relevant adhesion molecule involved in the recruitment and extravasation of leukocytes from circulating blood to inflamed joints (Conde et al., 2012).

Leptin also could contribute to abnormal osteoblast function in OA. In fact, the elevated production of leptin in OA abnormal subchondral osteoblast is correlated with the increased levels of ALP (alkaline phosphatase), OC (osteocalcin), collagen type I, and TGF-β1 (transforming growth factor β1), inducing a dysregulation of osteoblast function (Mutabaruka et al., 2010).

Leptin and leptin’s receptor expression levels were significantly increased in advanced OA cartilage and in SF (Vuolteenaho et al., 2012). Moreover, a very recent study showed that leptin bioactive levels are increased in SF from obese OA patients and SOCS-3 (a typically leptin-induced signaling suppressor in the cell) expression in cartilage is decreased in these patients compared with non-obese OA patients (Vuolteenaho et al., 2012).

Ku et al. (2009) have demonstrated a relationship of SF leptin concentrations with the radiographic severity of OA, suggesting a role of leptin as an effective marker for OA.

These results suggested that leptin might act as a pro-inflammatory factor on cartilage metabolism and exert a catabolic effect on OA joints. In recent studies, comparing the incidence rates of knee osteoarthritis between ob/ob and db/db mice and controls, no significant differences have been detected (Griffin et al., 2009). This recent finding suggested that obesity, per se, is not a sufficient condition to induce knee OA, whereas leptin is necessary in the development and progression of OA associated with obesity.

In fact, most studies support the role of the adipokines as a non-mechanical link between obesity and OA. In patients with clinical knee osteoarthritis, Berry et al. (2011) have demonstrated that leptin was significantly associated with increased levels of the bone formation biomarkers, such as osteocalcin and PINP, and reduced cartilage volume loss. In the same way, baseline expression of leptin receptors was associated with reduced levels of the cartilage formation biomarkers PIIANP, with increased cartilage defects score, and with increased cartilage volume loss. All these results were independent of age, sex, and body mass index.

Figure 1.

Figure 1. Schematic representation of the most relevant effects of leptin and adiponectin in osteoarthritis and rheumatoid arthritis.

However, in other recent published papers, no association between leptin levels and hand OA progression or severity has been demonstrated (Massengale et al., 2012; Yusuf et al., 2011). To note, some authors found a correlation between leptin serum concentration and the intensity of chronic hand OA pain (Massengale et al., 2012) (Figure 1).

Leptin and Rheumatoid Arthritis

Together with other neuroendocrine signals, leptin seems to play a role in autoimmune diseases such as RA, but whether leptin can harm or protect joint structures in RA is still unclear. In patients with RA, circulating leptin levels have been described as either higher or unmodified in comparison to healthy controls (Otero et al., 2006; Toussirot et al., 2007). In RA patients, a fasting-induced fall in circulating leptin is associated with CD4+ lymphocyte hyporeactivity and increased IL-4 secretion (Fraser et al., 1999). Experimental antigen-induced arthritis is less severe in leptin-deficient ob/ob mice than in wild-type mice, whereas leptin-deficient mice and leptin-receptor-deficient mice exhibited a delayed resolution of the inflammatory process in zymosan-induced experimental arthritis. Notably, leptin decreased the severity of septic arthritis in wild-type mice. So, in the light of the present results it seems difficult to make an unambiguous conclusion about a potential role of leptin in RA (Bernotiene et al., 2006). Several studies have also demonstrated that there may exist a close dependence between the risk of aggressive course of RA and leptin levels (Lee et al., 2007; Targonska-Stepniak et al., 2008). In addition, a correlation among serum leptin, synovial fluid/serum leptin ratio, disease duration, and parameters of RA activity has been reported (Olama et al., 2012).

It is relevant to mention that current biologic treatments for RA, such as anti-TNF (tumor necrosis factor) therapies, do not directly modulate leptin levels (Derdemezis et al., 2009; Gonzalez-Gay et al., 2009; Popa et al., 2009).

Also, it is important to note the relevance of leptin in vitro. Many studies demonstrated the effect of this adipokine in different cell types present in the joint. Apart from the prominent activity of leptin in chondrocytes, which was demonstrated by our group and others (Conde et al., 2012; Otero et al., 2003; 2005; 2007), leptin has more recently been shown to also exert a pro-inflammatory effect on synovial fibroblasts. Leptin induced IL-8 production in synovial fibroblasts via a mechanism involving a canonical activation of the leptin receptor and NF-κB (Tong et al., 2008). To note, this effect was also demonstrated by our group in human chondrocytes (Gomez et al., 2011).

The action of leptin in RA is not only targeted to articular tissue, this adipokine also exerts direct modulatory effects on activation, proliferation, maturation, and production of inflammatory mediators in a variety of immune cells, including lymphocytes, natural killer cells, monocytes/macrophages, dendritic cells, neutrophils, and eosinophils (Lam and Lu, 2007).

In particular, it is known that leptin is able to modulate regulatory T cells (Treg) that are potent suppressors of autoimmunity. Matarese and colleagues have recently demonstrated that leptin secreted by adipocytes sustains T helper 1 (Th1) immunity by promoting effector T cell proliferation and by constraining Treg cell expansion (De Rosa et al., 2007). Weight loss, with concomitant reduction in leptin levels, induces a reduction in effector T cell proliferation and an increased expansion of Treg cells, leading to a down-regulation of Th1 immunity and cell-mediated autoimmune diseases associated with increased susceptibility to infections. On the contrary, an increase in adipocyte mass leads to high leptin secretion, which results in expansion of effector T cells and reduction of Treg cells. This fact determines an overall enhancement of the pro-inflammatory immunity and of T cell-mediated autoimmune disorders. Though, leptin can be considered as a link among immune tolerance, metabolic function, and autoimmunity and future strategies aimed at interfering with leptin signaling may represent innovative therapeutic tools for autoimmune disorders.

Very recently it has been demonstrated that leptin can activate mammalian target of rapamycin (mTOR) and regulate the proliferative capacity of regulatory T cells. This study suggests that the leptin-mTOR signaling pathway is an important link between host energy status and Treg cell activity. Authors conclude that oscillating mTOR activity is necessary for Treg cell activation and suggest that this might explain why Treg cells are unresponsive to TCR stimulation in vitro when high levels of leptin and nutrients may sustain mTOR activation (Procaccini et al., 2010; De Rosa et al., 2007). To note, both direct and indirect effects of leptin on the immune system have been described to account for the immune defects observed in leptin- and leptin-receptor-deficient rodents. Actually, Palmer et al. (2006) have also shown an indirect effect of leptin on the immune system, demonstrating that leptin receptor deficiency affects the immune system indirectly via changes in the systemic environment (Figure 1).

Adiponectin

Adiponectin, also known as GBP28, apM1, Acrp30, or AdipoQ, is a 244-residue protein that is produced mainly by WAT. Adiponectin has structural homology with collagens VIII and X and complement factor C1q, and it circulates in the blood in relatively large amounts in different molecular forms (Kadowaki and Yamauchi, 2005; Oh et al., 2007).

It increases fatty acid oxidation and reduces the synthesis of glucose in the liver. Ablation of the adiponectin gene has no dramatic effect on knockout mice on a normal diet, but when placed on a high fat/sucrose diet, they develop severe insulin resistance and exhibit lipid accumulation in muscles.

Circulating adiponectin levels tend to be low in morbidly obese patients and increase with weight loss (Kadowaki and Yamauchi, 2005; Oh et al., 2007).

Adiponectin acts via two receptors, one (AdipoR1) found predominantly in skeletal muscle and the other (AdipoR2) in liver. Transduction of the adiponectin signal by AdipoR1 and AdipoR2 involves the activation of AMPK, PPAR-α, PPAR-γ, and other signaling molecules (Kadowaki and Yamauchi, 2005).

Adiponectin and Osteoarthritis

Some findings indicate that adiponectin has a wide range of effects in pathologies involving inflammation, such as cardiovascular disease, endothelial dysfunction, type 2 diabetes, metabolic syndrome, and OA (Matsuzawa, 2006). In contrast to its previously described protective role in vascular diseases, there are some lines of evidence that show that adiponectin might act as a pro-inflammatory factor in joints, and it could be involved in matrix degradation.

Adiponectin-treated chondrocytes lead to the induction of NOS2, via a signaling pathway that involves PI3 kinase. Similarly, this adipokine also increases the production of IL-6, MMP-3, MMP-9, and MCP-1 in the same cell type (Lago et al., 2008). Recently, the induction of MMP-3 by adiponectin in chondrocytes was further confirmed, and it occurred, in part, through p38, AMPK, and NF-κB (Tong et al., 2011). In addition, Kang et al. (2010) have reported that collagenase-cleaved type II collagen neoepitope, a product of collagen type II degradation, was increased in supernatants of adiponectin-induced OA cartilage explants. Furthermore, it has been reported that adiponectin is able to induce the expression of IL-6 in human synovial fibroblasts (Tang et al., 2007).

Like leptin, adiponectin was recently described as a potent inductor of VCAM-1 in chondrocytes, even more than a classic pro-inflammatory cytokine as IL-1β. So, it is reasonable to describe a scenario in which this adipokine is able to perpetuate cartilage-degrading processes by inducing molecules responsible for monocyte and leukocyte infiltration to the joint.

In addition, the implication of adiponectin in OA pathogenesis is supported by clinical observations. It has been reported that plasma adiponectin levels were significantly higher in OA patients than in healthy controls (Laurberg et al., 2009). Actually, Filkova et al. (2009) found higher adiponectin serum levels in erosive OA patients compared with non-erosive OA patients. In the same way, Koskinen et al. (2011a) reported that serum adiponectin and adiponectin synthesis from OA cartilage are higher in patients with the radiologically most severe disease. Furthermore, these authors and others observed an association among adiponectin serum levels, OA biomarkers and local synovial inflammation (de Boer et al., 2012; Koskinen et al., 2011a). To note, adiponectin-leptin ratio was proposed as predictor of pain in OA patients (Gandhi et al., 2010), in fact this adipokine has been detected in OA synovial fluids correlating with aggrecan degradation (Hao et al., 2011).

Also, it is noteworthy that there was an increase in IL-6 and adiponectin production in infrapatellar fat pad (IFP) in knee osteoarthritis (Klein-Wieringa et al., 2011a; Ushiyama et al., 2003; Distel et al., 2009), showing that IFP could contribute to the local production of cytokines and adipokines. Taken together, these results suggest that adiponectin may be considered a potential molecule involved in joint disorders and matrix degradation.

However, the role of adiponectin in OA is controversial. There are some findings that show an inhibition of IL-1β-induced MMP-13 expression and up-regulation of tissue inhibitor of metallopreoteinase-2 (TIMP-2) mediated by adiponectin in chondrocytes (Chen et al., 2006). Moreover, in STR/Ort mice, an animal osteoarthritis model, the serum adiponectin levels are lower compared with control group (Uchida et al., 2009), suggesting a protective role for this adipokine in the development of the disease.

It is noteworthy that clinical data also support the fact that adiponectin could be a protective molecule against OA. A recent study revealed an inverse correlation between adiponectin and disease severity (Honsawek and Chayanupatkul, 2010). Moreover, it has been reported that patients with high adiponectin levels had a decreased risk for hand OA progression, suggesting that this adipokine may be a protective hormone against cartilage damage (Yusuf et al., 2011). Although, other recent studies showed that serum adiponectin levels were not associated with radiographic hand OA severity (Massengale et al., 2012) (Figure 1).

Adiponectin and Rheumatoid Arthritis

The potential role of adiponectin in rheumatoid arthritis has been actively investigated. Generally, low adiponectin levels have been associated with obesity, type 2 diabetes, atherosclerosis, and vessel inflammation. Moreover, in metabolic syndrome the role of adiponectin is clearly anti-inflammatory. On the other side, multiple studies described high adiponectin levels in patients with RA, and these levels correlate with severity of RA (Alkadi et al., 2011; Otero et al., 2006; Ebina et al., 2009). Several authors identified an association between serum adiponectin levels and radiographic damage in patients with RA (Klein-Wieringa et al., 2011b; Giles et al., 2009). These findings suggest that this adipokine may be a mediator of the paradoxical relationship between increasing adiposity and protection from radiographic damage in RA. In addition, other studies reveal that adiponectin is also related to erosive joint destruction in RA (Giles et al., 2011), and it has been described that this adipokine is associated with the pro-inflammatory cytokine IL-6 (Oranskiy et al., 2012; Ozgen et al., 2010).

In contrast to its “protective” role against obesity and vascular diseases, at joint levels adiponectin might be pro-inflammatory. In synovial fibroblasts (SF), adiponectin induces IL-6 production and MMP-1, two of the main mediators of RA via the p38 MAPK pathway (Ehling et al., 2006). Similarly, IL-8 is induced by adiponectin through an intracellular pathway involving NF-κB (Gomez et al., 2011; Katano et al., 2009). In addition, adiponectin and IL-1β synergize in the induction of IL-6, IL-8, and prostaglandin E2 (PGE2) in RA synovial cells (Lee et al., 2012), suggesting that adiponectin and IL-1β may act synergistically in the induction of pro-inflammatory factors during RA progression.

Recent studies showed that adiponectin might also contribute to synovitis and joint destruction in RA by stimulating MMP-1, MMP-13, and vascular endothelial growth factor (VEGF) expression in synovial cells, surprisingly, more than conventional pro-inflammatory mediators (i.e., IL-1β) (Choi et al., 2009). In addition, a study developed in RA synovial fibroblasts (RASFs) showed that adiponectin increases both cyclooxygenase-2 (COX-2) and membrane-associated PGE synthase-1 (mPGES-1) mRNA and protein expression, resulting in an increase in PGE2 production in a time and concentration-dependent manner (Kusunoki et al., 2010). This increase was inhibited by siRNA against adiponectin receptor (AdipoR1 and AdipoR2) or using inhibitors of specific proteins involved in adiponectin signal transduction (Kusunoki et al., 2010). Recently, Frommer et al. (2010) have confirmed the pro-inflammatory role of adiponectin in RA by demonstrating that this adipokine promotes inflammation through cytokine synthesis by the different cells present in the joint. Also, it participates in the attraction of inflammatory cells to the synovium via chemokines synthesis and promoting matrix destruction due to the increased release of matrix metalloproteinases by chondrocytes. Moreover, the authors described that the different isoforms of adiponectin can induce the expression of different genes involved in the pathogenesis of RA (Frommer et al., 2012); these results suggest that adiponectin have detrimental effects in joint inflammatory diseases such as RA (Figure 1).

Other Adipokines in Osteoarthritis and Rheumatoid Arthritis

Chemerin. Chemerin, also known as tazarotene-induced gene 2 and retinoic acid receptor responder 2 (RARRES2), is a chemoattractant adipokine (Wittamer et al., 2003). It is secreted as an 18 kDa inactive proprotein and it is activated by posttranslational C-terminal cleavage (Wittamer et al., 2003). Chemerin acts via the G-coupled receptor chemokine-like receptor 1 (CMKLR1 or ChemR23) (Wittamer et al., 2003). Chemerin and its receptor are expressed mainly in adipose tissue (Bozaoglu et al., 2007), but also in, for instance, dendritic cells, and macrophages express chemerin receptor (Luangsay et al., 2009). ChemR23 is also expressed by endothelial cells, and it is up-regulated by pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 (Kaur et al., 2010).

Interestingly, chondrocytes express chemerin and its receptor (Berg et al., 2010; Conde et al., 2011), and IL-1β is able to increase chemerin expression (Conde et al., 2011). In the same way, Berg et al. (2010) have demonstrated that recombinant chemerin enhances the production of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-8), as well as different MMPs (MMP-1, MMP-2, MMP-3, MMP-8, and MMP-13) in human articular chondrocytes. These factors play a role in the degradation of the extracellular matrix, by causing a breakdown of the collagen and aggrecan framework, and result in the irreversible destruction of the cartilage in OA and RA. Moreover, these authors reported that recombinant chemerin phosphorylates p42/44 MAPK and Akt.

To note, chemerin was detected in synovial fluid from OA and RA patients (Eisinger et al., 2012; Huang et al., 2012), and the serum concentration of this adipokine was correlated with the disease severity in OA (Huang et al., 2012). Moreover, it has been reported that chemerin enhances the production of IL-6 and MMP-3 in fibroblast-like synoviocytes (Kaneko et al., 2011), suggesting a role for chemerin in the pathogenesis of RA. In addition, this adipokine stimulates the synthesis of CCL2 and TLR4 (Eisinger et al., 2012), and the authors postulated that chemerin develops certain functions in the relationship between innate immunity and joint inflammation.

Lipocalin 2. Lipocalin 2 (LCN2), also termed siderocalin, 24p3, uterocalin, and neutrophil gelatinase-associated lipocalin (NGAL), is a 25 kDa glycoprotein isolated from neutrophil granules although white adipose tissue (WAT) is thought to be the main source (Triebel et al., 1992). The LCN2 protein has been isolated as a 25 kDa monomer, as a 46 kDa homodimer, and in a covalent complex with MMP-9, and its cellular receptor, megalin (GP330), was described (Devireddy et al., 2001). LCN2 is involved in apoptosis of hematopoietic cells (Devireddy et al., 2001), transport of fatty acids and iron (Chu et al., 1998), modulation of inflammation (Cowland and Borregaard, 1997), among other processes.

LCN2 has recently been identified in chondrocytes (Owen et al., 2008). In these cells IL-1β, leptin, adiponectin, LPS, and dexamethasone act as potent modulators of LCN2 expression (Conde et al., 2011). LCN2 is likely to be involved in matrix degradation since it forms molecular complexes with MMP-9 (Gupta et al., 2007).

Recently, the group of Katano confirmed that the level of NGAL in SF was significantly higher in patients with RA than in those with osteoarthritis. Through proteome analysis Katano et al. (2009) have showed that GM-CSF may contribute to the pathogenesis of RA by the up-regulation of LCN2 in neutrophils, followed by induction of Cathepsin D, transitional endoplasmic reticulum ATPase (TERA), and transglutaminase 2 (tg2) in synoviocytes. These enzymes may contribute to the proliferation of synovial cells and infiltration of inflammatory cells inside the synovium.

Vaspin. Vaspin is a serpin (serine protease inhibitor) that was produced in the visceral adipose tissue (Hida et al., 2005). Interestingly, administration of vaspin to obese mice improved glucose tolerance and insulin sensitivity and reversed altered expression of genes that might promote insulin resistance. The induction of vaspin by adipose tissue might constitute a compensatory mechanism in response to obesity and its inflammatory complications.

With regard to rheumatic diseases, serum vaspin concentrations were increased in RA patients compared to healthy controls (Ozgen et al., 2010). Moreover, synovial fluid vaspin levels were significantly higher in RA patients compared to OA patients (Senolt et al., 2010).

Apelin. Apelin is a bioactive peptide that was originally identified as the endogenous ligand of the orphan G protein- coupled receptor APJ (Tatemoto et al., 1998). TNF increases apelin productions in both adipose tissue and blood plasma when administered to mice (Daviaud et al., 2006).

Hu et al. (2010) have suggested that apelin may play a catabolic role in cartilage metabolism. Apelin stimulates the proliferation of chondrocytes and significantly increases the mRNA expression of the catabolic factors MMP-1, MMP-3, MMP-9, and IL-1β in vitro. Intra-articular injection with apelin in vivo up-regulates the expression of MMP-3, MMP-9, and IL-1β in articular cartilage. By contrast, apelin treatment decreases the level of collagen II in the same tissue. In addition, after treatment with apelin, mRNA levels of ADAMTS-4 and ADAMTS-5 in articular cartilage are markedly increased and depletion of proteoglycan in articular cartilage was found.

Also, the same group reported that serum apelin levels were higher in OA patients compared with healthy controls (Hu et al., 2011). Moreover, this adipokine was present in the synovial fluid of these patients and correlated positively with disease activity (Hu et al., 2011). These results indicate that apelin could contribute to the development of OA.

Omentin. Omentin is a protein of 40 kDa secreted by omental adipose tissue and highly abundant in human plasma that had previously been identified as intelectin, a new type of Ca2+-dependent lectin with affinity to galactofuranosyl residues (which are constituents of pathogens and dominant immunogens) (Schaffler et al., 2005). So, it was suggested that a biological function of omentin/intelectin was the specific recognition of pathogens and bacterial components, playing an important role in the innate immune response to parasite infection (Gerwick et al., 2007). Moreover, several studies have shown that omentin gene expression is altered by inflammatory states and obesity (de Souza Batista et al., 2007).

Senolt et al. (2010) have found reduced levels of omentin in the synovial fluid of patients with RA compared with those with OA. In addition, it has been demonstrated that synovial fluid omentin concentrations were negatively correlated with the severity of the OA (Li et al., 2012; Xu et al., 2012), suggesting that this adipokine could serve as a biomarker for reflecting the severity of the disease.

Conclusions

The study of adipokines opened a new perspective of how molecules secreted by adipose tissue could affect the joint structures in rheumatic diseases. The relationship between obesity and rheumatic diseases such as OA has been considered just by a higher mechanical stress. However, the discovery of these adipose-derived factors demonstrated a metabolic relationship too. In the last several years there have been many studies trying to identify new adipokines and their signaling pathways, as well as, their actions in the different joint tissues.

All of the knowledge about these proteins could aid the development of new pharmacological treatments, for instance, the use of specific antibodies in a similar way to anti-TNF-α therapy. Also, with the data presented in this review we could conclude that adipokines might serve as biomarkers of the severity of certain rheumatic diseases.

This area of research is ongoing and more future research studies will be necessary to clarify the specific functions of adipokines in rheumatic diseases.

Acknowledgment

The work of O.G. and F.L. is funded by Instituto de Salud Carlos III and Xunta de Galicia (SERGAS) through a research-staff stabilization contract. O.G. is supported by Instituto de Salud Carlos III and Xunta de Galicia (grants PI11/01073 and 10CSA918029PR). F.L. is supported by Instituto de Salud Carlos III [grants PI11/00497 and REDINSCOR (RD06/0003/0016)]. This work was also partially supported by the RETICS Program, RD08/0075 (RIER) via Instituto de Salud Carlos III (ISCIII), within the VI NP of R+D+I 2008-2011 (OG). J.C. is a recipient of a fellowship from the Foundation IDIS-Ramón Dominguez. M.S. is a recipient of the “FPU” Program of the Spanish Ministry of Education. R.G. is a recipient of the “Sara Borrell Program” of the Spanish National Institute of Health “Carlos III.” V.L. is a recipient of a grant from Xunta de Galicia.

Disclosure

The authors report no conflicts of interest.

Corresponding Author

Oreste Gualillo, Pharm.D., Ph.D., NEIRID Lab (NeuroEndocrine Interaction in Rheumatology and Inflammatory Diseases), SERGAS, Santiago University Clinical Hospital, Institute of Medical Research (IDIS), Santiago de Compostela, Spain.

References

Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 382(6588):250-252, 1996.

Alkady EA, Ahmed HM, Tag L, Abdou MA. [Serum and synovial adiponectin, resistin, and visfatin levels in rheumatoid arthritis patients. Relation to disease activity]. Z Rheumatol 70(7):602-608, 2011.

Bao JP, Chen WP, Feng J, Hu PF, Shi ZL, Wu LD. Leptin plays a catabolic role on articular cartilage. Mol Biol Rep 37(7):3265-3272, 2010.

Berg V, Sveinbjornsson B, Bendiksen S, Brox J, Meknas K, Figenschau Y. Human articular chondrocytes express ChemR23 and chemerin; ChemR23 promotes inflammatory signalling upon binding the ligand chemerin(21-157). Arthritis Res Ther 12(6):R228, 2010.

Bernotiene E, Palmer G, Gabay C. The role of leptin in innate and adaptive immune responses. Arthritis Res Ther 8(5):217, 2006.

Berry PA, Jones SW, Cicuttini FM, Wluka AE, Maciewicz RA. Temporal relationship between serum adipokines, biomarkers of bone and cartilage turnover, and cartilage volume loss in a population with clinical knee osteoarthritis. Arthritis Rheum 63(3):700-707, 2011.

Bozaoglu K, Bolton K, McMillan J, Zimmet P, Jowett J, Collier G, Walder K, Segal D. Chemerin is a novel adipokine associated with obesity and metabolic syndrome. Endocrinology 148(10):4687-4694, 2007.

Conde J, Gomez R, Bianco G, Scotece M, Lear P, Dieguez C, Gomez-Reino J, Lago F, Gualillo O. Expanding the adipokine network in cartilage: identification and regulation of novel factors in human and murine chondrocytes. Ann Rheum Dis 70(3):551-559, 2011.

Conde J, Scotece M, Lopez V, Gomez R, Lago F, Pino J, Gomez-Reino JJ, Gualillo O. Adiponectin and leptin induce vcam-1 expression in human and murine chondrocytes. PLoS One 7(12):e52533, 2012.

Cowland JB, Borregaard N. Molecular characterization and pattern of tissue expression of the gene for neutrophil gelatinase-associated lipocalin from humans. Genomics 45(1):17-23, 1997.

Chen TH, Chen L, Hsieh MS, Chang CP, Chou DT, Tsai SH. Evidence for a protective role for adiponectin in osteoarthritis. Biochim Biophys Acta 1762(8):711-718, 2006.

Choi HM, Lee YA, Lee SH, Hong SJ, Hahm DH, Choi SY, Yang HI, Yoo MC, Kim KS. Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators. Arthritis Res Ther 11(6):R161, 2009.

Chu ST, Lin HJ, Huang HL, Chen YH. The hydrophobic pocket of 24p3 protein from mouse uterine luminal fluid: fatty acid and retinol binding activity and predicted structural similarity to lipocalins. J Pept Res 52(5):390-397, 1998.

Daviaud D, Boucher J, Gesta S, Dray C, Guigne C, Quilliot D, Ayav A, Ziegler O, Carpene C, Saulnier-Blache JS, Valet P, Castan-Laurell I. TNFalpha up-regulates apelin expression in human and mouse adipose tissue. FASEB J 20(9):1528-1530, 2006.

de Boer TN, van Spil WE, Huisman AM, Polak AA, Bijlsma JW, Lafeber FP, Mastbergen SC. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage 20(8):846-853, 2012.

De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, La Cava A, Matarese G. A key role of leptin in the control of regulatory T cell proliferation. Immunity 26(2):241-255, 2007.

de Souza Batista CM, Yang RZ, Lee MJ, Glynn NM, Yu DZ, Pray J, Ndubuizu K, Patil S, Schwartz A, Kligman M, Fried SK, Gong DW, Shuldiner AR, Pollin TI, McLenithan JC. Omentin plasma levels and gene expression are decreased in obesity. Diabetes 56(6):1655-1661, 2007.

Derdemezis CS, Filippatos TD, Voulgari PV, Tselepis AD, Drosos AA, Kiortsis DN. Effects of a 6-month infliximab treatment on plasma levels of leptin and adiponectin in patients with rheumatoid arthritis. Fundam Clin Pharmacol 23(5):595-600, 2009.

Devireddy LR, Teodoro JG, Richard FA, Green MR. Induction of apoptosis by a secreted lipocalin that is transcriptionally regulated by IL-3 deprivation. Science 293(5531):829-834, 2001.

Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X, Benelli C. The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor. Arthritis Rheum 60(11):3374-3377, 2009.

Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, Pottie P. Evidence for a key role of leptin in osteoarthritis. Arthritis Rheum 48(11):3118-3129, 2003.

Ebina K, Fukuhara A, Ando W, Hirao M, Koga T, Oshima K, Matsuda M, Maeda K, Nakamura T, Ochi T, Shimomura I, Yoshikawa H, Hashimoto J. Serum adiponectin concentrations correlate with severity of rheumatoid arthritis evaluated by extent of joint destruction. Clin Rheumatol 28(4):445-451, 2009.

Edwards C, Rogers A, Lynch S, Pylawka T, Silvis M, Chinchilli V, Mosher T, Black K. The effects of bariatric surgery weight loss on knee pain in patients with osteoarthritis of the knee. Arthritis 2012:504189, 2012.

Ehling A, Schaffler A, Herfarth H, Tarner IH, Anders S, Distler O, Paul G, Distler J, Gay S, Scholmerich J, Neumann E, Muller-Ladner U. The potential of adiponectin in driving arthritis. J Immunol 176(7):4468-4478, 2006.

Eisinger K, Bauer S, Schaffler A, Walter R, Neumann E, Buechler C, Muller-Ladner U, Frommer KW. Chemerin induces CCL2 and TLR4 in synovial fibroblasts of patients with rheumatoid arthritis and osteoarthritis. Exp Mol Pathol 92(1):90-96, 2012.

Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 115(5):911-919; quiz 920, 2005.

Filkova M, Liskova M, Hulejova H, Haluzik M, Gatterova J, Pavelkova A, Pavelka K, Gay S, Muller-Ladner U, Senolt L. Increased serum adiponectin levels in female patients with erosive compared with non-erosive osteoarthritis. Ann Rheum Dis 68(2):295-296, 2009.

Fraser DA, Thoen J, Reseland JE, Forre O, Kjeldsen-Kragh J. Decreased CD4+ lymphocyte activation and increased interleukin-4 production in peripheral blood of rheumatoid arthritis patients after acute starvation. Clin Rheumatol 18(5):394-401, 1999.

Frommer KW, Zimmermann B, Meier FM, Schroder D, Heil M, Schaffler A, Buchler C, Steinmeyer J, Brentano F, Gay S, Muller-Ladner U, Neumann E. Adiponectin-mediated changes in effector cells involved in the pathophysiology of rheumatoid arthritis. Arthritis Rheum 62(10):2886-2899, 2010.

Frommer KW, Schaffler A, Buchler C, Steinmeyer J, Rickert M, Rehart S, Brentano F, Gay S, Muller-Ladner U, Neumann E. Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis? Ann Rheum Dis 71(10):1724-1732, 2012.

Gandhi R, Takahashi M, Syed K, Davey JR, Mahomed NN. Relationship between body habitus and joint leptin levels in a knee osteoarthritis population. J Orthop Res 28(3):329-333, 2010.

Gerwick L, Corley-Smith G, Bayne CJ. Gene transcript changes in individual rainbow trout livers following an inflammatory stimulus. Fish Shellfish Immunol 22(3):157-171, 2007.

Giles JT, Allison M, Bingham CO, 3rd, Scott WM, Jr, Bathon JM. Adiponectin is a mediator of the inverse association of adiposity with radiographic damage in rheumatoid arthritis. Arthritis Rheum 61(9):1248-1256, 2009.

Giles JT, van der Heijde DM, Bathon JM. Association of circulating adiponectin levels with progression of radiographic joint destruction in rheumatoid arthritis. Ann Rheum Dis 70(9):1562-1568, 2011.

Gomez R, Scotece M, Conde J, Gomez-Reino JJ, Lago F, Gualillo O. Adiponectin and leptin increase IL-8 production in human chondrocytes. Ann Rheum Dis 70(11):2052-2054, 2011.

Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Vazquez-Rodriguez TR, Miranda-Filloy JA, Gonzalez-Juanatey C, de Matias JM, Martin J, Dessein PH, Llorca J. Short-term effect of anti-TNF-alpha therapy on nitric oxide production in patients with severe rheumatoid arthritis. Clin Exp Rheumatol 27(3):452-458, 2009.

Griffin TM, Huebner JL, Kraus VB, Guilak F. Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. Arthritis Rheum 60(10):2935-2944, 2009.

Grotle M, Hagen KB, Natvig B, Dahl FA, Kvien TK. Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up. BMC Musculoskelet Disord 9:132, 2008.

Gualillo O, Eiras S, Lago F, Dieguez C, Casanueva FF. Elevated serum leptin concentrations induced by experimental acute inflammation. Life Sci 67(20):2433-2441, 2000.

Gupta K, Shukla M, Cowland JB, Malemud CJ, Haqqi TM. Neutrophil gelatinase-associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9. Arthritis Rheum 56(10):3326-3335, 2007.

Hao D, Li M, Wu Z, Duan Y, Li D, Qiu G. Synovial fluid level of adiponectin correlated with levels of aggrecan degradation markers in osteoarthritis. Rheumatol Int 31(11):1433-1437, 2011.

Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS. Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc Natl Acad Sci U S A 102(30):10610-10615, 2005.

Honsawek S, Chayanupatkul M. Correlation of plasma and synovial fluid adiponectin with knee osteoarthritis severity. Arch Med Res 41(8):593-598, 2010.

Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87-91, 1993.

Hu PF, Chen WP, Tang JL, Bao JP, Wu LD. Apelin plays a catabolic role on articular cartilage: in vivo and in vitro studies. Int J Mol Med 26(3):357-363, 2010.

Hu PF, Tang JL, Chen WP, Bao JP, Wu LD. Increased apelin serum levels and expression in human chondrocytes in osteoarthritic patients. Int Orthop 35(9):1421-1426, 2011.

Huang K, Du G, Li L, Liang H, Zhang B. Association of chemerin levels in synovial fluid with the severity of knee osteoarthritis. Biomarkers 17(1):16-20, 2012.

Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA. Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases. Ann Rheum Dis 71(3):455-462, 2012.

Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev 26(3):439-451, 2005.

Kaneko K, Miyabe Y, Takayasu A, Fukuda S, Miyabe C, Ebisawa M, Yokoyama W, Watanabe K, Imai T, Muramoto K, Terashima Y, Sugihara T, Matsushima K, Miyasaka N, Nanki T. Chemerin activates fibroblast-like synoviocytes in patients with rheumatoid arthritis. Arthritis Res Ther 13(5):R158, 2011.

Kang EH, Lee YJ, Kim TK, Chang CB, Chung JH, Shin K, Lee EY, Lee EB, Song YW. Adiponectin is a potential catabolic mediator in osteoarthritis cartilage. Arthritis Res Ther 12(6):R231, 2010.

Katano M, Okamoto K, Arito M, Kawakami Y, Kurokawa MS, Suematsu N, Shimada S, Nakamura H, Xiang Y, Masuko K, Nishioka K, Yudoh K, Kato T. Implication of granulocyte-macrophage colony-stimulating factor induced neutrophil gelatinase-associated lipocalin in pathogenesis of rheumatoid arthritis revealed by proteome analysis. Arthritis Res Ther 11(1):R3, 2009.

Kaur J, Adya R, Tan BK, Chen J, Randeva HS. Identification of chemerin receptor (ChemR23) in human endothelial cells: chemerin-induced endothelial angiogenesis. Biochem Biophys Res Commun 391(4):1762-1768, 2010.

Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM, Yusuf E, Kwekkeboom JC, El-Bannoudi H, Nelissen RG, Zuurmond A, Stojanovic-Susulic V, Van Osch GJ, Toes RE, Ioan-Facsinay A. The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. Ann Rheum Dis 70(5):851-857, 2011a.

Klein-Wieringa IR, van der Linden MP, Knevel R, Kwekkeboom JC, van Beelen E, Huizinga TW, van der Helm-van Mil A, Kloppenburg M, Toes RE, Ioan-Facsinay A. Baseline serum adipokine levels predict radiographic progression in early rheumatoid arthritis. Arthritis Rheum 63(9):2567-2574, 2011b.

Koskinen A, Juslin S, Nieminen R, Moilanen T, Vuolteenaho K, Moilanen E. Adiponectin associates with markers of cartilage degradation in osteoarthritis and induces production of proinflammatory and catabolic factors through mitogen-activated protein kinase pathways. Arthritis Res Ther 13(6):R184, 2011a.

Koskinen A, Vuolteenaho K, Nieminen R, Moilanen T, Moilanen E. Leptin enhances MMP-1, MMP-3 and MMP-13 production in human osteoarthritic cartilage and correlates with MMP-1 and MMP-3 in synovial fluid from OA patients. Clin Exp Rheumatol 29(1):57-64, 2011b.

Ku JH, Lee CK, Joo BS, An BM, Choi SH, Wang TH, Cho HL. Correlation of synovial fluid leptin concentrations with the severity of osteoarthritis. Clin Rheumatol 28(12):1431-1435, 2009.

Kusunoki N, Kitahara K, Kojima F, Tanaka N, Kaneko K, Endo H, Suguro T, Kawai S. Adiponectin stimulates prostaglandin E(2) production in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 62(6):1641-1649, 2010.

Lago F, Dieguez C, Gomez-Reino J, Gualillo O. Adipokines as emerging mediators of immune response and inflammation. Nat Clin Pract Rheumatol 3(12):716-724, 2007.

Lago R, Gomez R, Otero M, Lago F, Gallego R, Dieguez C, Gomez-Reino JJ, Gualillo O. A new player in cartilage homeostasis: adiponectin induces nitric oxide synthase type II and pro-inflammatory cytokines in chondrocytes. Osteoarthritis Cartilage 16(9):1101-1109, 2008.

Lam QL, Lu L. Role of leptin in immunity. Cell Mol Immunol 4(1):1-13, 2007.

Laurberg TB, Frystyk J, Ellingsen T, Hansen IT, Jorgensen A, Tarp U, Hetland ML, Horslev-Petersen K, Hornung N, Poulsen JH, Flyvbjerg A, Stengaard-Pedersen K. Plasma adiponectin in patients with active, early, and chronic rheumatoid arthritis who are steroid- and disease-modifying antirheumatic drug-naive compared with patients with osteoarthritis and controls. J Rheumatol 36(9):1885-1891, 2009.

Lee SW, Park MC, Park YB, Lee SK. Measurement of the serum leptin level could assist disease activity monitoring in rheumatoid arthritis. Rheumatol Int 27(6):537-540, 2007.

Lee YA, Choi HM, Lee SH, Yang HI, Yoo MC, Hong SJ, Kim KS. Synergy between adiponectin and interleukin-1beta on the expression of interleukin-6, interleukin-8, and cyclooxygenase-2 in fibroblast-like synoviocytes. Exp Mol Med 44(7):440-447, 2012.

Li ZG, Zhao DW, Xia CJ, Wang TN, Liu YP, Zhang Y, Wang BJ. Decreased synovial fluid omentin-1 concentrations reflect symptomatic severity in patients with knee osteoarthritis. Scand J Clin Lab Invest 72(8):623-628, 2012.

Luangsay S, Wittamer V, Bondue B, De Henau O, Rouger L, Brait M, Franssen JD, de Nadai P, Huaux F, Parmentier M. Mouse ChemR23 is expressed in dendritic cell subsets and macrophages, and mediates an anti-inflammatory activity of chemerin in a lung disease model. J Immunol 183(10):6489-6499, 2009.

Massengale M, Lu B, Pan JJ, Katz JN, Solomon DH. Adipokine hormones and hand osteoarthritis: radiographic severity and pain. PLoS One 7(10):e47860, 2012.

Matsuzawa Y. Therapy Insight: adipocytokines in metabolic syndrome and related cardiovascular disease. Nat Clin Pract Cardiovasc Med 3(1):35-42, 2006.

Mutabaruka MS, Aoulad Aissa M, Delalandre A, Lavigne M, Lajeunesse D. Local leptin production in osteoarthritis subchondral osteoblasts may be responsible for their abnormal phenotypic expression. Arthritis Res Ther 12(1):R20, 2010.

Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 9(3):282-289, 2007.

Olama SM, Senna MK, Elarman M. Synovial/serum leptin ratio in rheumatoid arthritis: the association with activity and erosion. Rheumatol Int 32(3):683-690, 2012.

Oranskiy SP, Yeliseyeva LN, Tsanaeva AV, Zaytseva NV. Body composition and serum levels of adiponectin, vascular endothelial growth factor, and interleukin-6 in patients with rheumatoid arthritis. Croat Med J 53(4):350-356, 2012.

Otero M, Gomez Reino JJ, Gualillo O. Synergistic induction of nitric oxide synthase type II: in vitro effect of leptin and interferon-gamma in human chondrocytes and ATDC5 chondrogenic cells. Arthritis Rheum 48(2):404-409, 2003.

Otero M, Lago R, Lago F, Reino JJ, Gualillo O. Signalling pathway involved in nitric oxide synthase type II activation in chondrocytes: synergistic effect of leptin with interleukin-1. Arthritis Res Ther 7(3):R581-R591, 2005.

Otero M, Lago R, Gomez R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Changes in plasma levels of fat-derived hormones adiponectin, leptin, resistin and visfatin in patients with rheumatoid arthritis. Ann Rheum Dis 65(9):1198-1201, 2006.

Otero M, Lago R, Gomez R, Lago F, Gomez-Reino JJ, Gualillo O. Phosphatidylinositol 3-kinase, MEK-1 and p38 mediate leptin/interferon-gamma synergistic NOS type II induction in chondrocytes. Life Sci 81(19-20):1452-1460, 2007.

Owen HC, Roberts SJ, Ahmed SF, Farquharson C. Dexamethasone-induced expression of the glucocorticoid response gene lipocalin 2 in chondrocytes. Am J Physiol Endocrinol Metab 294(6):E1023-E1034, 2008.

Ozgen M, Koca SS, Dagli N, Balin M, Ustundag B, Isik A. Serum adiponectin and vaspin levels in rheumatoid arthritis. Arch Med Res 41(6):457-463, 2010.

Palmer G, Aurrand-Lions M, Contassot E, Talabot-Ayer D, Ducrest-Gay D, Vesin C, Chobaz-Peclat V, Busso N, Gabay C. Indirect effects of leptin receptor deficiency on lymphocyte populations and immune response in db/db mice. J Immunol 177(5):2899-2907, 2006.

Popa C, Netea MG, de Graaf J, van den Hoogen FH, Radstake TR, Toenhake-Dijkstra H, van Riel PL, van der Meer JW, Stalenhoef AF, Barrera P. Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis. J Rheumatol 36(4):724-730, 2009.

Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A, Carbone F, Fontana S, Horvath TL, La Cava A, Matarese G. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33(6):929-941, 2010.

Schaffler A, Neumeier M, Herfarth H, Furst A, Scholmerich J, Buchler C. Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochim Biophys Acta 1732(1-3):96-102, 2005.

Senolt L, Polanska M, Filkova M, Cerezo LA, Pavelka K, Gay S, Haluzik M, Vencovsky J. Vaspin and omentin: new adipokines differentially regulated at the site of inflammation in rheumatoid arthritis. Ann Rheum Dis 69(7):1410-1411, 2010.

Tang CH, Chiu YC, Tan TW, Yang RS, Fu WM. Adiponectin enhances IL-6 production in human synovial fibroblast via an AdipoR1 receptor, AMPK, p38, and NF-kappa B pathway. J Immunol 179(8):5483-5492, 2007.

Targonska-Stepniak B, Majdan M, Dryglewska M. Leptin serum levels in rheumatoid arthritis patients: relation to disease duration and activity. Rheumatol Int 28(6):585-591, 2008.

Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251(2):471-476, 1998.

Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6(10):772-783, 2006.

Tong KM, Shieh DC, Chen CP, Tzeng CY, Wang SP, Huang KC, Chiu YC, Fong YC, Tang CH. Leptin induces IL-8 expression via leptin receptor, IRS-1, PI3K, Akt cascade and promotion of NF-kappaB/p300 binding in human synovial fibroblasts. Cell Signal 20(8):1478-1488, 2008.

Tong KM, Chen CP, Huang KC, Shieh DC, Cheng HC, Tzeng CY, Chen KH, Chiu YC, Tang CH. Adiponectin increases MMP-3 expression in human chondrocytes through AdipoR1 signaling pathway. J Cell Biochem 112(5):1431-1440, 2011.

Toussirot E, Streit G, Wendling D. The contribution of adipose tissue and adipokines to inflammation in joint diseases. Curr Med Chem 14(10):1095-1100, 2007.

Triebel S, Blaser J, Reinke H, Tschesche H. A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinase. FEBS Lett 314(3):386-388, 1992.

Uchida K, Urabe K, Naruse K, Ogawa Z, Mabuchi K, Itoman M. Hyperlipidemia and hyperinsulinemia in the spontaneous osteoarthritis mouse model, STR/Ort. Exp Anim 58(2):181-187, 2009.

Ushiyama T, Chano T, Inoue K, Matsusue Y. Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids. Ann Rheum Dis 62(2):108-112, 2003.

Vincent HK, Heywood K, Connelly J, Hurley RW. Obesity and weight loss in the treatment and prevention of osteoarthritis. PM R 4(5 Suppl):S59-S67, 2012.

Vuolteenaho K, Koskinen A, Moilanen T, Moilanen E. Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis. Ann Rheum Dis 71(11):1912-1913, 2012.

Wittamer V, Franssen JD, Vulcano M, Mirjolet JF, Le Poul E, Migeotte I, Brezillon S, Tyldesley R, Blanpain C, Detheux M, Mantovani A, Sozzani S, Vassart G, Parmentier M, Communi D. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J Exp Med 198(7):977-985, 2003.

Wluka AE, Lombard CB, Cicuttini FM. Tackling obesity in knee osteoarthritis. Nat Rev Rheumatol, epub ahead of print, Dec. 18, 2012.

Xu L, Zhu GB, Wang L, Wang DF, Jiang XR. Synovial fluid omentin-1 levels are inversely correlated with radiographic severity of knee osteoarthritis. J Investig Med 60(3):583-586, 2012.

Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, van Osch G, Middeldorp S, Huizinga TW, Kloppenburg M. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis 69(4):761-765, 2010.

Yusuf E, Ioan-Facsinay A, Bijsterbosch J, Klein-Wieringa I, Kwekkeboom J, Slagboom PE, Huizinga TW, Kloppenburg M. Association between leptin, adiponectin and resistin and long-term progression of hand osteoarthritis. Ann Rheum Dis 70(7):1282-1284, 2011.

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425-432, 1994.

[Discovery Medicine; ISSN: 1539-6509; Discov Med 15(81):73-83, February 2013. Copyright © Discovery Medicine. All rights reserved.]

Access This PDF as a Subscriber |
Close
Close
E-mail It
Close